Preclinical Imaging Of Prostate Cancer Using Radiolabeled Antibodies PDF Download

Prostate cancer diagnosis and treatment options need to be improved as over- and under-treatment, as well as disease recurrence and resistance to current therapies, continue to be challenges. Prostate stem cell antigen (PSCA) is overexpressed in the majority of prostate cancers and correlates with grade, stage, and metastatic potential. Antibodies, which are highly specific for their target, can be labeled with radionuclides and fluorophores for molecular imaging and therapy. This dissertation describes the use of humanized anti-PSCA antibody fragments for dual-modality immuno-positron emission tomography (immunoPET)/fluorescence imaging and for radioimmunotherapy of prostate cancer in preclinical models. Prostate cancer visualization could be improved by using immunoPET for preoperative non-invasive disease detection, and fluorescence imaging for intraoperative guidance of tumor resection; the power of both imaging modalities can be combined on a single agent. In this work, the dual-labeled humanized anti-PSCA A11 cys-minibody (A11 cMb) was evaluated for successive immunoPET/fluorescence imaging in subcutaneous and orthotopic prostate cancer models. A11 cMb was site-specifically conjugated with the near-infrared fluorophore Cy5.5 and radiolabeled with 124I or 89Zr. 124I- and 89Zr-A11 cMb-Cy5.5 were used to detect subcutaneous and intraprostatic PSCA-positive tumors. High contrast immunoPET/fluorescence imaging with 124I-A11 cMb-Cy5.5 identified both high PSCA-expression and moderate PSCA-expression subcutaneous tumors. 89Zr-A11 cMb-Cy5.5 immunoPET showed uptake in the prostate without interfering signal in the bladder, and ex vivo fluorescence imaging clearly showed signal in the tumor and not the surrounding seminal vesicles. These studies support the potential for dual-modality A11 cMb to be translated for preoperative whole-body disease detection and real-time surgical guidance in prostate cancer patients. Prostate cancer that metastasizes often becomes resistant to current therapies and eventually progresses, and alternative therapy options include radioimmunotherapy which delivers a high radiation dose to the tumor with the aim of minimizing dose to normal organs. Anti-PSCA antibody fragments radiolabeled with a cytotoxic radionuclide, such as the beta-emitter 131I or 177Lu, may be effective for radioimmunotherapy with lower toxicity compared to intact antibodies. 124I- and 89Zr-A11 minibody (A11 Mb) immunoPET was used to guide dosimetry studies, and 131I- and 177Lu-A11 Mb was administered to 22Rv1-PSCA s.c. tumor-bearing nude mice to complete dosimetry estimation. 131I-A11 Mb had a higher projected therapeutic index, or tumor-to-radiosensitive tissue dose, and was used in subsequent therapy studies. 131I-A11 Mb inhibited PSCA-positive tumor growth in a dose-dependent manner and extended survival with minimal off-target toxicity. Additionally, preliminary biodistribution studies in knock-in transgenic mice that express human-PSCA were similar to that of nude mice. Therefore, radioimmunotherapy will likely not be toxic to organs with normal PSCA expression (stomach, bladder), and A11 Mb may be suitable for human translation. The results of this work demonstrate the potential of anti-PSCA minibodies as theranostic agents for disease diagnosis, surgical guidance, and treatment. Additionally, the success of anti-PSCA dual-modality imaging and radioimmunotherapy in preclinical models support further evaluation in the clinic.